We propose to form a Drug Discovery Group For the Treatment of Cognitive Impairment Associated with Alzheimer's Disease (DDG-AD). The overall goal is to identify targets that mediate pathogenic molecular events in Alzheimer's Disease (AD), and develop potential drug candidates for AD. The focus of this DDG-AD will be the discovery of distinct neural protease enzymes that mediate abnormal and pathogenic processes in AD, and the development of inhibitors of these proteases as drugs for AD. This DDG-AD will be a highly collaborative effort, integrating many disciplines ranging from chemistry, biochemistry and structural biophysics, to molecular and cellular neurobiology, immunodiagnostics, transgenics and behavioral neuropharmacology. In order to achieve the overall goals of this program, we propose to carry out six scientific projects. In Project 1, probe molecules will be designed to identify target neural proteases, and the three-dimensional structure of these proteases will be solved, enabling rational structure-based drug design. Project 2 will evaluate brain tissue and cerebrospinal fluid to correlate the presence of target neural proteases with the known AD marker, ADAP. Project 2 also will develop diagnostic CSF assays to enable early identification of AD patients. Project 3 will carry out the identification, purification and characterization of unique AD-associated proteases, and establish assay methodology to evaluate target efficacy of designed protease inhibitors. Project 4 will utilize molecular biology-based strategies to establish the molecular basis of abnormal neural protease involvement in AD. Project 4 also will generate DNA constructs for development of transgenic mice that exhibit AD-associated pathology, for use in behavioral studies and drug evaluation. Project 5 will investigate the cellular role of abnormal neural proteases in the processing of amyloid precursor protein, and in other neuronal processes, and will assess the effects of protease inhibitors on these processes. Project 6 will establish the molecular basis for truncation of the nerve growth factor receptor, including the identification of the responsible protease(s), and investigate the role of this process in AD-related neurodegeneration. The six projects will be source tissue for target proteases, and serve as a reference resource for precise clinical identification of disease state (normal, AD, or non-AD dementia). Core C will provide biotechnology support such as protein sequencing, nucleotide sequencing and synthesis, and production of monoclonal antibodies. Core D will support efforts to generate transgenic "Alzheimer's mice", and evaluate their pathology, in collaboration with Projects 1, 3, 4 and 6. Core F will provide neuropharmacology support to evaluate potential inhibitor candidates, and behavioral evaluation on transgenic mice. The primary research emphasis of this program will be target identification and inhibitor design, however, substantial medicinal chemistry and related activities will be mobilized by Abbott at the appropriate time to expedite development of a clinical drug candidate for AD.